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Pharmacology > Superfamily 4 > Flashcards

Superfamily 4 Flashcards

1
Q

What receptors are included in SF 4?

A

Intracellular/ nuclear receptors

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2
Q

How large is superfamily 4?

A

It is a small superfamily
It has less that 50 types of receptors
Compared to SF 2 with 900,000

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3
Q

How is SF 4 divided?

A

Class l
Class ll
Hybrid class

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4
Q

What type of receptor is in class l?

A

Receptors for steroid hormones
E.G oestrogen receptor family
Glucocorticoid hormone receptor (cortisol)
Mineralocorticoid hormone receptor (aldosterone)
Androgen receptors
Progesterone receptors

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5
Q

What receptors are part of class ll?

A

Receptors for lipid mediators already in the cell
LXR
PPARs
FXR
SXR
Orphan nuclear receptors

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6
Q

What is the LXR receptor?

A

Liver oxysterol receptor
Cholesterol sensor

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7
Q

What is the PPAR receptor?

A

Peroxidase proliferator activated receptors for fatty acids

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8
Q

What is the FXR receptor?

A

The farnesoid receptor for bile acids

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9
Q

What is the SXR receptor?

A

Steroid and xenobiotic receptor
Regulates the clearance of drugs

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10
Q

Give an example of an orphan nuclear receptor in class ll

A

RXR retinoid receptor for derivatives of retinoic acid

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11
Q

What type of receptors belong to the hybrid class of SF 4?

A

Miscellaneous receptors that are mainly for endocrine mediators

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12
Q

What receptors are found in the hybrid class?

A

Thyroid hormone receptor
Vitamin D receptor
Retinoic acid (vit A) receptor
All lipophilic

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13
Q

What is the significant difference in SF 4s structure?

A

There are no transmembrane alpha helixes
Because it is found completely intracellularly
It’s a single protein chain

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14
Q

Where will the ligand bind to in SF 4 receptor?

A

Close to the C terminal
The activation function 2 site
Other ligands May bind here too to anchor them within the cell (especially in the receptors inactive state)

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15
Q

Explain what the regulatory domain is

A

found at the N terminal, activation function 1 site (ligands may use this as a scaffold) changes to this region may alter the activity of the receptor

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16
Q

Explain what the zinc fingers are and where they’re found

A

Found at the DNA binding domain
There are two zinc fingers
Zinc atom surrounded by 15 amino acids
Folded when the receptor is inactive
When the receptor changes shape due to activation the fingers will open up and act as little hooks for nucleic acids to hook onto

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17
Q

Where are class l nuclear receptors found?

A

Mainly present in the cytoplasm, sometimes located at the nuclear membrane and perinuclear region .
Will be complexed with heat shock protein 90 in the absence of a ligand to keep it anchored in the right place

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18
Q

Which ligands do Class l receptors recognise?

A

They mainly recognise and have high affinity for endocrine ligands

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19
Q

How will class l receptors operate?

A

They operate as homodimers on activation
Allosteric interactions may be important for receptor activity or cooperativity

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20
Q

How can class l receptors act as transcription factors?

A

When it activated by ligand binding the zinc fingers open and can attach to nucleic acids to a hormone responsive element upstream of the promoter region
This allows it to regulate gene transcription

21
Q

How does the ligand activated receptor regulate transcription?

A

Can activate genes or repress constitutively expressed genes on binding to HRE
Often involved in negative feedback gene expression
Can increase or decrease expression of its own or of others steroid hormone receptors

22
Q

How does the steroid hormone travel?

A

Steroid hormone is quite lipophilic
It travels in the blood by binding to steroid hormone binding globulins which deliver it to the ligand cell membrane where it can easily diffuse into the cell

23
Q

What happens once steroid hormone diffuses into the cell?

A

The Steroid hormone will bind to an unoccupied receptor causing it to irreversibly dissociate from the heat shock 90 protein
The allosteric change in shape due to activation will unmask the zinc fingers

24
Q

What are the properties of class ll nuclear receptors?

A

They’re already present in the nucleus (often bind to DNA in the absence of a ligand)
Frequently operate as heterodimers
Mainly recognise lipid ligands already present in the cell
Low affinity ligand binding site

25
Q

What do class ll nuclear receptors do?

A

Tend to mediate positive feedback and amplification
Ligand promotes dissociation of receptor from DNA to remove inhibition of gene expression influencing the positive feedback
Will often influence expression of enzymes influencing metabolism of lipids and of prescription drugs

26
Q

How does methylation work to co-regulate gene expression

A

DNA methylation silences gene expression
Demethylating enzymes can enhance expression

27
Q

How does acetylation work as Co-regulators of gene expression?

A

Deacetylation of histones suppresses gene expression by winding DNA more tightly together
Acetylating enzymes will enhance expression

28
Q

What conditions are mutations of methylating and acteylating enzymes associated with?

A

Inflammatory disease
Malignancies

29
Q

List some of the therapeutic potentials of oestrogens

A

Control of reproductive function
Bone metabolism
Cardiovascular disease
Alzheimer’s disease
Hot flushes, mood changes

30
Q

What are the splice variants of the oestrogen receptor?

A

ER alpha
ER beta

31
Q

What are the difference between ER alpha and ER beta?

A

They differ in regard to tissue distribution
There is less than 30% overlap in the genes which they regulate
Thought to be selective for different co activators and co repressors
ER beta is found in the mitochondrial genome and can influence mitochondrial genes

32
Q

What agents are being identified for nuclear receptor therapeutics?

A

Selective nuclear receptor modulators (SNuRMs)
Selective nuclear receptor degraders (SNuRDs)

33
Q

What do SNuRMs do?

A

Activate subset of functions of natural ligand
So natural ligands can let all coregulators and cosupressors bind
Similar to agonist trafficking
The modulator will only activate a subset of functions that the natural ligand would activate

34
Q

Give two examples of SNuRMs

A

Raloxifene
Tamoxifen

35
Q

How does raloxifene work?

A

Acts as an agonist at oestrogen receptors in some tissues such as bone to prevent post menopausal osteoporosis
Acts as an oestrogen receptor antagonist in other tissues such as the uterus and breasts to reduce the incidence and progression of cancer

36
Q

What other possible uses are there for SNuRMs?

A

SNuRMs could be useful for other steroid hormone receptors for example to separate androgenic and anabolic effects of androgenic receptors

37
Q

Explain the example of tamoxifen as a SNuRM

A

Tamoxifen acts as an oestrogen receptor antagonist to help slow the progression of breast cancer
However resistance emerges after two years on the treatment
At this point it will change from being an oestrogen antagonist to an oestrogen agonist which is counter productive in the fight against breast cancer

38
Q

What are theories to explain the change of tamoxifens activity?

A

Preferential survival/ proliferation of mutant receptors with different coregulator profiles
Temporal alterations in expression or activity of coregulators
Altered acetylation of histones or methylation of DNA would influence which coregulators bind
Phosphorylation of the receptor or of coregulators by GPCR activated or tyrosine kinase receptors dependent protein kinases

39
Q

What do SNuRDs do?

A

They regulate cell nuclear receptor turnover

40
Q

How are SNuRDs used?

A

As therapeutic strategies to down regulate receptor numbers in conditions associated with nuclear receptor over expression

41
Q

Give an example of a SNuRD

A

Fluvestrant
Used for eostrogen receptor positive metastatic breast cancer

42
Q

Why is there thought to be a cell surface oestrogen receptor as well as the intracellular nuclear receptors?

A

Some say that the response seen from oestrogen receptor activation are too quick to be reliant on gene expression

43
Q

What are the theories behind an extracellular oestrogen receptor?

A

Translocation of the intracellular oestrogen receptor to the cell surface membrane
Due to genome sequencing it is now known that there is G protein coupled receptor known as GPR-30 for oestrogen associated with activation of adenylate cyclase and phospholipase C-beta

44
Q

What is the significance of the GPR-30 receptor?

A

It is implicated in some oestrogen signalling pathways including cardioprotection, neuro protection and bone preservation
The signal transduction is independent of direct interaction of the receptor with genome - does not require protein synthesis

45
Q

Give some examples of recent nuclear receptor therapeutics

A

Spirolactone
Rosiglitazone
Fibrates
SXR modulators

46
Q

What is spirolactone?

A

An aldosterone receptor antagonist
Reduces sodium leading to fluid loss in order to aid in heart failure

47
Q

What is rosiglitazone?

A

A PPAR gamma agonist as a novel anti diabetic agent
It has insulin sensitising action

48
Q

How do fibrates work?

A

They are PPAR alpha agonists to treat dyslipidaemia
They reduce serum triglyceride levels

49
Q

How do SXR modulators work? Steroid and xenobiotic receptor modulator

A

Would decrease enzyme activity to prolong the drugs time of action, it would not be cleared as quickly
This could improve a particular drugs efficacy
Could change the distribution of the drug by skipping the first pass metabolism and increase the drugs bioavailability

Pharmacology (18 decks)

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